The international normalized ratio (INR): What reagent, what instrument? The assessment of the agreement between INR values according to different reagent/instrument combinations.

WHAT IS KNOWN AND OBJECTIVE: The international normalized ratio (INR) is widely used to monitor patients on vitamin K antagonists. This study aimed to assess the agreement of INR values obtained with different thromboplastin/instrument combinations. MATERIAL AND METHODS: International normalized ratio was determined on plasmas from 330 patients undergoing antivitamin K treatment (with acenocoumarol), using two calibration methods and four reagent/instrument combinations: Both Neoplastine CI and Neoplastine CI Plus on STA-R instrument from Diagnostica STAGO, Asnières, France; and both Thromborel S and Innovin on SYSMEX 2100i instrument from Siemens Health Care Diagnostics, Marbung, Germany. The agreement analysis was done using the Bland-Altman plot and the Cohen Kappa coefficient. RESULTS: The mean of the differences between the INR values and the limits of agreement were -0.07 [-0.51 to 0.38] for the Neoplastine CI plus and Neoplastine CI reagents, -0.08 [-1.18 to 1.03] for the Thromborel S and Innovin reagents when the INR was calculated, -0.1 [-1.15 to 0.95] for the Thromborel S and Innovin reagents when the INR was directly calibrated and -0.1 [-0.7 to 0.5] for the Neoplastine CI plus and Thromborel S. Cohen's kappa coefficients were 0.94, 0.76, 0.85 and 0.82, respectively. NEW FINDINGS AND CONCLUSION: The agreement between the four reagent/instrument combinations was high enough to classify patients as inefficaciously or efficaciously anticoagulated. The data interpretation should always be related to the clinical purpose.

Pharmacokinetic and pharmacodynamic evaluation of ramelteon : an insomnia therapy.

INTRODUCTION: Ramelteon , a selective melatonin receptor agonist, is the first member of a novel class of hypnotics. It is approved for the treatment of insomnia characterized by sleep onset difficulties in the US and Japan, but not in Europe. AREAS COVERED: The main clinical properties as well as safety issues of ramelteon are described. Relevant publications reporting ramelteon characteristics and its use in insomnia disorder were identified using PubMed and SciFinder databases up to January 2015. Additional information was collected from the US clinical trials database and from Takeda website. EXPERT OPINION: Despite its high prevalence and economic burden, insomnia disorder remains mostly untreated. Ramelteon has demonstrated sleep-promoting effects in clinical trials and clinical practice, and it is not associated with the adverse effects typical of other class of hypnotics. Its efficacy appears to be relatively modest compared to current insomnia therapeutics, and its use seems restricted to patients with sleep onset difficulties. Assessment of ramelteon effects on sleep quality and maintenance, daytime function and of improvements in comorbid insomnia conditions deserves further studies. The potential application of ramelteon in other pathological conditions could open the way to novel therapeutic approaches as well as to new market opportunities.

Economic evaluation of apixaban for the prevention of stroke in non-valvular atrial fibrillation in the Netherlands.

BACKGROUND: Stroke prevention is the main goal of treating patients with atrial fibrillation (AF). Vitamin-K antagonists (VKAs) present an effective treatment in stroke prevention, however, the risk of bleeding and the requirement for regular coagulation monitoring are limiting their use. Apixaban is a novel oral anticoagulant associated with significantly lower hazard rates for stroke, major bleedings and treatment discontinuations, compared to VKAs. OBJECTIVE: To estimate the cost-effectiveness of apixaban compared to VKAs in non-valvular AF patients in the Netherlands. METHODS: Previously published lifetime Markov model using efficacy data from the ARISTOTLE and the AVERROES trial was modified to reflect the use of oral anticoagulants in the Netherlands. Dutch specific costs, baseline population stroke risk and coagulation monitoring levels were incorporated. Univariate, probabilistic sensitivity and scenario analyses on the impact of different coagulation monitoring levels were performed on the incremental cost-effectiveness ratio (ICER). RESULTS: Treatment with apixaban compared to VKAs resulted in an ICER of €10,576 per quality adjusted life year (QALY). Those findings correspond with lower number of strokes and bleedings associated with the use of apixaban compared to VKAs. Univariate sensitivity analyses revealed model sensitivity to the absolute stroke risk with apixaban and treatment discontinuations risks with apixaban and VKAs. The probability that apixaban is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 68%. Results of the scenario analyses on the impact of different coagulation monitoring levels were quite robust. CONCLUSIONS: In patients with non-valvular AF, apixaban is likely to be a cost-effective alternative to VKAs in the Netherlands.

[Prescription and follow-up of antithrombotic treatment with vitamin K antagonists]. / Prescription et suivi d'un traitement anticoagulant par les antivitamines K.

The indications for antithrombotic treatment with vitamin K antagonists are now relatively precise, but management of this treatment is often difficult in clinical practice and be set by problems such as unstable hypocoagulability, an increased bleeding risk, interactions with other therapies and pathologies, and high-level vitamin K intake in the diet. Rigorous and accurate information of the patient and family, along with regular and frequent control of the international normalized ratio (INR), are essential for the safety and efficacy of this treatment. Some physicians cite an excessive bleeding risk as one reason for withholding oral anticoagulation therapy from older patients with atrial fibrillation. Indeed, with the increasing aging of the population, and poor therapeutic observance, there is an increased risk of hemorragic adverse effects. However, vitamin K antagonists are associated with a significant reduction in embolic events, and recent guidelines recommend their prescription for elderly patients with atrial fibrillation. Their impact on the risk of thromboembolic events is well documented, with better results than those obtained with new oral anticoagulants. Education of the patient and family, and close cooperation between the patient, family, physician and entire medical team, are essential for the safety and efficacy of this treatment.

[Local haemostasis with an adhesive cyanoacrylate-coated membrane following tooth extraction in patients under anticoagulant or anti-platelet therapy]. / Hémostase locale par membrane enduite de cyanoacrylate, après avulsions dentaires sous anticoagulants ou anti-agrégants.

OBJECTIVE: Assessment of a local hemostasis with a compressive, extemporaneous gutter glued to the alveolar crest after tooth avulsion in patients under anticoagulant and/or platelet aggregation inhibitors, and economical impact of this technique. MATERIAL AND METHOD: Ninety-seven tooth extractions were performed in patients under AVK and/or anti-platelet drugs. The interventions were consecutive and concerned 251 teeth (138 different alveolar sites). The extraction alveolus was protected by an absorbable oxycellulose membrane coated with sterilized cyanoacrylate adhesive for medical use. This procedure was used with all patients, whatever the hemorrhagic risk (the only inclusion criterion was INR less than 4 for patients under AVK). All procedures were performed under local anesthesia. RESULTS: There was one hemorrhagic complication (0.72%) due to mechanical gutter destruction by an antagonist tooth. The adhesive did not run, there was no tissue necrosis, and no wound infection requiring gutter removal. DISCUSSION: This local hemostasis procedure is reliable. It may be an alternative to substitution of heparin, without or with hospitalization. This procedure, requiring modification of treatment, greatly decreases healthcare costs. Contra-indications include the presence of an antagonist tooth harmful for the gutter, and patients with impaired consciousness or tongue dyspraxia.

Ramelteon: application withdrawn. Ramelteon in insomnia: withdrawal of marketing application in patients' best interests.

The European Committee for Medicinal Products for Human Use (CHMP) has issued a negative opinion on the use of the melatonin receptor agonist ramelteon in insomnia, due to its unfavourable risk-benefit balance. In France, melatonin itself is licensed for use in this indication.

Ramelteon for the treatment of insomnia.

BACKGROUND: Insomnia is a common sleep disorder with a significant potential for deleterious effects on activities of daily living, productivity, and overall quality of life. Ramelteon, a highly selective agonist for melatonin subtypes 1 and 2 receptors, is a hypnotic agent approved by the US Food and Drug Administration (FDA) for the treatment of insomnia characterized by difficulty falling asleep. OBJECTIVE: This article reviews the pharmacokinetic properties, efficacy, and tolerability of ramelteon in the treatment of insomnia characterized by difficulty falling asleep. METHODS: Relevant articles were identified through searches of MEDLINE (1966 to July 2006), International Pharmaceutical Abstracts (January 1970 to July 2006), EMBASE Drugs and Pharmacology (1980 to third quarter 2006), and Current Contents/Clinical Medicine (2005 week 32 to 2006 week 31). Search terms included ramelteon, TAK-375, melatonin agonist, melatonin receptor agonist, insomnia, and sleep disorders/drug therapy (MeSH). RESULTS: A literature search revealed 12 randomized, controlled clinical trials that examined the efficacy or tolerability of ramelteon. In addition, 17 studies were reviewed for pharmacology and pharmacokinetic data. The references of the clinical trials and recent review articles were examined to ensure the comprehensiveness of the literature search. In 2 trials of patients with primary insomnia, patients treated with ramelteon 4 to 32 mg had significant reductions in latency to persistent sleep (LPS) compared with placebo (P < 0.001). Additionally, improvements in total sleep time (TST) were observed (P < 0.001), although increases in TST were noted only on nights 1-2 of the second study. Similarly, improvement in sleep efficiency was reported only on nights 1-2 of the second trial (P < 0.001). In elderly patients with primary insomnia, significant reductions in subjective LPS were observed with ramelteon 4 and 8 mg (P = 0.008); however, average subjective LPS was >70 minutes. Mean reported TST was significantly increased in the 4-mg group (P = 0.004). A second study in elderly patients found decreases in LPS with ramelteon 4 mg (P < 0.001) and 8 mg (P < 0.01), as well as significant increases in TST (P < 0.05 and P < 0.01, respectively). Sleep efficiency improved for patients treated with 4 mg (P < 0.05) and 8 mg (P < 0.01). Overall, the mean decrease in LPS reported in trials of ramelteon ranged from 10 to 19 minutes, and the mean increase in TST was 8 to 22 minutes. The most common adverse events observed with ramelteon included headache (7%), dizziness (5%), somnolence (5%), fatigue (4%), and nausea (3%). No evidence of cognitive impairment, rebound insomnia, withdrawal effects, or abuse potential was noted. CONCLUSIONS: Based on this review, ramelteon, the first FDA-approved melatonin receptor agonist, represents a pharmacologic option for the treatment of insomnia characterized by difficulty falling asleep. In patients with insomnia, treatment with ramelteon was generally well tolerated and resulted in modest but statistically significant decreases in LPS. In the absence of published trials comparing ramelteon with other sedative-hypnotic agents, it is not yet possible to determine its efficacy relative to other therapeutic options for insomnia.

The simultaneous assessment of four nonsteroidal antiinflammatory drugs in rheumatoid arthritis using a simple and rapid trial design. Australasia Multicentre Trial Group.

We compared naproxen and sulindac with salicylates, ibuprofen and placebo in the treatment of rheumatoid arthritis. The active medications were significantly more effective than placebo but not different from one another. Both naproxen and sulindac appeared to be more effective in the higher doses studied but a considerable variation in response emphasizes the need to individualize the dose requirements. A single-blind, non cross-over trial technique utilizing entirely subjective measurements in the form of self-assessment charts is presented. The method is simple and rapid and can be used for the simultaneous comparison of a number of antirheumatic drugs.